RheumShorts: Vasculitis, MRI, Anakinra for Knees

Action Points

Intra-articular inhibition of IL-1, but not inhibition of TNF, significantly reduced cartilage degeneration, synovial inflammation, and did not alter bone morphology following articular fracture.

In a retrospective study, rituximab was an effective remission-inducing agent in relapsing granulomatosis with polyangiitis.

The rheumatology literature this week explored whether or not patients with vasculitis treated with rituximab also need maintenance therapy, if MRI can predict later arthritis when disease is still subclinical, and how an interleukin (IL)-1 blocker could help in post-traumatic arthritis.

Rituximab With Maintenance

Patients with granulomatosis with polyangiitis (GPA) treated with rituximab (Rituxan) had fewer relapses if they also received maintenance therapy with conventional agents such as methotrexate or azathioprine, a retrospective study showed.

At 18 months after the first course of rituximab, 65% of patients on maintenance therapy remained in remission, compared with 39% of patients not receiving the additional treatment, according to Lama Azar, MD, and colleagues from the Cleveland Clinic.

After adjusting for sex, previous treatment with cyclophosphamide, antibody status, and prednisone dose, the adjusted hazard ratio for relapse among patients on maintenance therapy was 0.43 (95% CI 0.22-0.84), the researchers reported online in Arthritis and Rheumatology.

Granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) is a systemic inflammatory disease that can lead to the formation of granulomas and tissue necrosis, most often in the kidneys and respiratory tract.

Conventional treatment has involved high-dose steroids and a course of cyclophosphamide as induction therapy, followed by maintenance therapy with methotrexate or azathioprine. Cessation of treatment leads to relapse in the majority of patients.

Rituximab has emerged as a potential less toxic alternative to cyclophosphamide, but relapses also occur with this B-cell depleting agent, and the role for maintenance therapy has not been fully established.

Accordingly, Azar's group analyzed outcomes from their cohort of 105 patients, whose mean age was 49 and whose disease duration averaged 55 months. At the time of rituximab treatment, they had experienced a mean of three previous relapses, and had a mean duration of cyclophosphamide exposure of 8 months.

The treatment regimen consisted of four weekly doses of rituximab (375 mg/m2) or two fixed doses of 1,000 mg given at a 2-week interval. Median follow-up was 23 months.

A total of 97% of the patients were in complete remission 3 months after the initial course of rituximab, but 48% had at least one relapse, at a median time of 13 months post-treatment.

No additional immunosuppression was given to 42 patients, while the remainder were on azathioprine, methotrexate, or, in a few cases, mycophenolate mofetil (CellCept).

The median dose of prednisone was 5 mg per day at 6 months, and 25% of patients no longer needed prednisone at that point.

The relapses were considered major in five cases in the maintenance therapy group and in ten in the rituximab-only group.

There were no significant differences in the incidence of adverse events between the groups, with four serious infections in the maintenance group and three in the rituximab group.

A total of 55 patients had repeat courses of rituximab, and almost all once again achieved remission.

Another option for prevention of relapse in this vasculitis is routine "pre-emptive" repeat courses of rituximab, but that approach risks overtreating patients who might not relapse, which in this cohort included 14% who had no relapses for 2 years or more.

"There is an important unmet need to identify how these patients can be distinguished from the great majority of those with GPA who will require chronic maintenance therapy," the researchers noted.

Other questions also remain, including long-term safety, the optimal timing for introducing maintenance therapy, and how to judge an individual patient's risk-benefit ratio.

Until data become available to address those questions, "for patients with relapsing GPA who are treated with rituximab and glucocorticoids and who achieve remission, our data support the addition of a conventional maintenance agent in the absence of contraindications or intolerance, to reduce the risk of relapse," they concluded.

MRI to Predict RA?

Among patients with nonspecific arthralgia and autoantibodies suggestive of rheumatoid arthritis, the use of MRI wasn't accurate for predicting which patients might go on to develop the clinical disease.

Among a group of 28 patients who had MRI scans at baseline, 12 subsequently were diagnosed with rheumatoid arthritis. All but one of the 12 had abnormalities detected on MRI -- as did all 16 of the patients who didn't develop clinical arthritis, according to Conny J. van der Laken, MD, PhD, of VU University Medical Center in Amsterdam, and colleagues.

The extraordinary success of early treatment of rheumatoid arthritis has prompted interest in identifying patients during the first months of symptom onset, or even while the disease is still subclinical.

Because MRI can detect signs of inflammation in the joints before radiographic changes can be visualized, van der Laken and colleagues enrolled 28 patients and four healthy volunteers, obtaining MRI scans of the proximal interphalangeal, metacarpophalangeal, and wrist joints.

A scan was considered positive if synovitis or bone marrow edema was visualized.

Most of the patients were women, median age was 44, and median duration of the arthralgia symptoms was 15 months.

Ten of the patients had synovitis scores of 2 in at least one joint, and all four controls had synovitis scores of 1, meaning mild changes. One control had a score of 2 in one joint.

There did appear to be a temporal relationship between having synovitis scores of 2 and the development of rheumatoid arthritis, in that clinical disease appeared within a year among those with scores of 2 and more slowly over the 3-year follow-up in those with scores of 1.

However, this finding was not statistically significant, according to the investigators.

Increasing age was associated with higher MRI scores, with significant differences seen for patients older than 44 (B=0.39, P=0.038), but no association was seen for gender.

The higher MRI scores found in older patients "are likely to be related to the presence of degenerative changes in joints," the researchers explained.

They noted that MRI did appear to be sensitive for the detection of subclinical inflammatory changes, but the frequency of synovitis scores of 1, even in healthy individuals, requires clarification before MRI can be considered a suitable tool for preclinical evaluation of rheumatoid arthritis.

A limitation of the study was the small number of patients and controls.

Post-Traumatic Arthritis

Acute blockade of interleukin (IL)-1 may represent a means of preventing post-traumatic osteoarthritis in the knee joint, a mouse study suggested.

In a murine model of post-traumatic arthritis of the knee joint, intra-articular administration of the interleukin (IL)-1 receptor antagonist anakinra (Kineret) was associated with few degenerative changes and no difference from the contralateral limb on histopathologic Mankin scores, according to Steven A. Olson, MD, and colleagues from Duke University.

Approximately 12% of cases of knee osteoarthritis are the result of injury, and post-injury arthritis is the single most common cause for U.S. service personnel being unable to return to duty.

While post-traumatic arthritis can result from various types of injury, including torn ligaments, articular fractures are of particular concern because "they commonly and predictably cause accelerated joint degeneration." Current treatment usually requires surgery.

However, it is now recognized that high levels of pro-inflammatory cytokines such as IL-1 and tumor necrosis factor (TNF) are found in the acutely injured joint.

Therefore, to see if targeting these cytokines could alter the expected joint degeneration, Olson's group conducted a series of experiments in which they administered the post-fracture knees of mice with saline, anakinra, or a TNF inhibitor, either as single injections or systemically for a month.

Local injection of the TNF inhibitor was less effective than the IL-1 blocker, with fibrocartilage being identified at the site of fracture, along with deterioration of cartilage structure and loss of proteoglycans.

The intra-articular injection of anakinra also did not interfere with bone healing, the researchers noted.

"These results show that intra-articular IL-1, rather than TNF-alpha, plays a critical role in the acute inflammatory phase following joint injury and can be inhibited locally to reduce post-traumatic arthritis following a closed articular fracture," they stated.

Systemic administration of saline had similar effects as the local saline injection, and systemic treatment with the TNF inhibitor continued to show loss of cartilage and proteoglycans.

But systemic administration of the IL-1 blocker "was associated with significant degenerative changes with frequent complete loss of articular cartilage and the presence of fibrocartilage," and higher Mankin scores than with either saline (P=0.0001) or the TNF inhibitor (P=0.007).

This worsening of joint changes with longer-term administration of anakinra suggests "that IL-1 may transition from playing a negative role in the acute phase of trauma to a positive role in the healing and bone remodeling phase," the researchers noted.

Their results "support the therapeutic benefit of a novel method of treating acute joint injuries that may be used as adjunctive therapy to surgical stabilization," they concluded.

Azar and colleagues disclosed no relevant relationships with industry.

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